Effective glomerular filtration pressure and single nephron filtration rate during hydropenia, elevated ureteral pressure, and acute volume expansion with isotonic saline.

Free-flow and stop-flow intratubular pressures were measured in rats with an improved Gertz technique using Landis micropipets or a Kulite microtransducer. In hydropenia, average single nephron glomerular filtration rate was 29.3 nl/min, glomerular hydrostatic pressure (stop-flow pressure + plasma colloid osmotic pressure) was 70 cm H(2)O and mean glomerular effective filtration pressure was 12.7-14.3 cm H(2)O, approaching zero at the efferent end of the glomerulus. Thus, the glomerulus is extremely permeable, having a filtration coefficient four to five times greater than previously estimated. Mean effective filtration pressure and single nephron glomerular filtartion rate fell with elevated ureteral pressure and rose with volume expansion, more or less proportionately. Changes in effective filtration pressure were due primarily to increased intratubular pressure in ureteral obstruction and to reduced plasma colloid osmotic pressure in volume expansion; glomerular hydrostatic pressure remained constant in both conditions and thus played no role in regulation of filtration rate.

Glomerular hemodynamics in persistent renovascular hypertension in the rat.

We studied the glomerular hemodynamics and activity of the tubuloglomerular feedback system (TGFS) in Wistar rats with persistent hypertension 60 days after removal of the clipped kidney in the Goldblatt (two-kidney, one clip) hypertension model. Ten hypertensive rats (HBP) were compared with 12 normotensive ones (NBP). Micropuncture studies revealed that values for the single nephron glomerular filtration rate (SNGFR), glomerular plasma flow (QA), and afferent oncotic pressure (PAR.A) were similar in both groups, whereas glomerular capillary pressure (PGC) and effective filtration pressure (EFP) were higher in the HBP group (p less than 0.05). A slight but insignificant increase in afferent resistance was present in the HBP group. A positive correlation was found between mean arterial pressure and stop flow pressure (SFP) (r = 0.64, p less than 0.05) but not with SNGFR, suggesting a reduction in the ultrafiltration coefficient in hypertensive rats. This was further supported by studies of the activity of the TGFS, which demonstrated that interrupting flow to the macula densa was followed by a smaller increment in SNGFR in HBP, in spite of a similar rise in SFP. The mechanism responsible for decreasing glomerular permeability is unknown but could be related to structural changes in glomerular capillary or to an increase in intrarenal angiotensin II, as has been demonstrated previously in this model. It is suggested that these adaptations occurring in the kidney exposed to hypertension can contribute to the maintenance of elevated arterial pressure after removing the stenotic kidney.

Evaluating hyperfiltration with glycine in hypertensive rats with renal ablation.

Hypertension-induced renal damage is mediated by increased glomerular pressure and flow. These alterations have been evaluated by the renal response to protein or amino acids. To test this assumption, we studied glomerular hemodynamic responses to glycine infusion in rats with reduced renal mass, with and without Goldblatt hypertension. The left kidney was ablated by two thirds in 12 rats, and in 5, hypertension was induced by clipping the right renal artery. Seven normal, unmanipulated rats served as controls. Micropuncture was performed in the left kidney during control and 15% glycine infusion periods, 45 days after surgery. Arterial pressure was higher in hypertensive rats (160.3 mm Hg) than in controls (103.8 mm Hg) and rats with renal ablation (125 mm Hg; p less than 0.05). Higher values of single-nephron glomerular filtration rate and single-nephron plasma flow in rats with renal ablation (63.0, 223.7 nl/min) and hypertension (46.1, 239.7 nl/min) than in controls (28.8, 94.9; p less than 0.05) demonstrated the presence of hyperfiltration. However, glomerular pressure was elevated only in hypertensive rats (40.1 mm Hg), when compared to controls (32.7 mm Hg; p less than 0.05) and rats with renal ablation (33.4 mm Hg; p less than 0.05). Glycine increased single-nephron glomerular filtration rate and single-nephron plasma flow in control rats by 76 and 65%; rats with renal ablation had only partial responses, 35% and 23%, respectively, whereas in hypertensive rats the response was completely abolished. Glycine detected hyperfiltration and unmasked a dysfunction of preglomerular vessels that was greater in hypertensive rats and could contribute to the rise in glomerular pressure and flow and thereby to glomerular damage.

Pentosan polysulfate treatment reduces cyclosporine-induced nephropathy in salt-depleted rats.

BACKGROUND: Long-term cyclosporine (CsA) treatment leads to a decreased glomerular filtration rate, hyalinosis of afferent arterioles, and striped cortical tubulo-interstitial fibrosis. We showed previously that pentosan polysulfate (SP54) prevented the development of microvascular and interstitial lesions in mouse models of progressive glomerulosclerosis. In this study, we examined the effect of pentosan polysulfate on the development of CsA nephropathy. METHODS: Pair-fed Sprague-Dawley rats were fed a low-sodium (0.03%) diet and received CsA (15 mg/kg, subcutaneously, in olive oil)/5% glucose, pentosan polysulfate (10 mg/kg, subcutaneously in 5% glucose) plus CsA, olive oil/pentosan polysulfate, or olive oil/5% glucose for 30 days. Creatinine clearance (CrCl) was determined at three time points. Afferent arteriolar lesions, glomerular volume, and tubulo-interstitial lesions were quantitated. RNA was extracted from cortex. RESULTS: Severe lesions were found in the CsA group. A reduction in the number of affected arterioles (32%) and the degree of chronic tubulo-interstitial lesions (44%) was found in pentosan polysulfate/CsA-treated rats. A 20% decrease in glomerular volume was found in CsA rats, but not in pentosan polysulfate/CsA-treated rats. Pentosan polysulfate treatment did not prevent the CsA-induced decrease in CrCl (approximately 30%) at 4 weeks. CsA did not affect cortical endothelial or neuronal nitric-oxide synthase or mRNA levels, but there was small increase in neuronal nitric-oxide synthase mRNA levels in the pentosan polysulfate/CsA-treated group. CONCLUSIONS: Pentosan polysulfate reduced structural renal lesions in CsA-treated, salt-depleted Sprague-Dawley rats.

Enalapril in essential hypertension.

It is now well recognised that the renin-angiotensin system plays a key role in the control of blood pressure not only through circulating angiotensin II but through its interaction with the autonomic and central nervous systems. Angiotensin-converting enzyme (ACE) inhibitors have proved to be effective in lowering blood pressure in different types of hypertension. This study evaluates the antihypertensive effects of enalapril, a new, potent, long acting ACE inhibitor. 50 patients with uncomplicated essential hypertension were included in 4 groups. Group I was used to compare the effects of enalapril and propranolol on blood pressure, renal function, plasma renin activity, aldosterone excretion and plasma lipids in 24 patients after 23 weeks. Group II was used to evaluate long term effects (48 weeks) of these drugs in 13 patients. Group III included 32 patients that received enalapril as monotherapy for 6 to 12 weeks. Group IV was studied to estimate the antihypertensive effect of low doses of hydrochlorothiazide in 18 patients receiving enalapril. The effect on mean blood pressure was similar with enalapril and propranolol (enalapril 117 versus 103 mm Hg and propranolol 115 versus 104 mm Hg); however, the glomerular filtration rate decreased with propranolol (105 versus 87 ml/min; p less than 0.05) and was unaltered with enalapril (102 versus 98 ml/min). Triglycerides rose with propranolol (179 versus 231 mg/dl; p less than 0.05) and did not change with enalapril (157 versus 121 mg/dl). In the long term, antihypertensive effects were similar and no significant side effects were observed. In 14/32 patients blood pressure became normal with enalapril alone. Low doses of hydrochlorothiazide (12.5 to 25 mg) decreased mean blood pressure by 10mm Hg when added to enalapril. The antihypertensive effect of enalapril was similar to that of propranolol; however, the lowering effect on glomerular filtration rate of propranolol did not occur with enalapril. A slight rise in triglycerides occurred only with propranolol. No significant side effects were observed with either propranolol or enalapril. Used as monotherapy, enalapril normalised blood pressure in 44% of cases. Addition of low doses of hydrochlorothiazide significantly increased the antihypertensive effect of enalapril.

Mechanisms involved in the progression to glomerular sclerosis induced by systemic hypertension during mild puromycin aminonucleoside nephrosis.

To evaluate the contribution of systemic hypertension in the progression of nephropathies to glomerular sclerosis, a mild form of puromycin aminonucleoside (PAN) nephrosis was associated with Goldblatt hypertension and studied after 18 weeks. We studied four groups: Group I, controls; Group II, Goldblatt hypertension; Group III, PAN nephrosis; and Group IV, both conditions. Systolic blood pressure, 24-h proteinuria, serum cholesterol, triglycerides, glomerular hemodynamics, and histological studies were compared among the groups. Rats in groups II and IV developed systemic hypertension, but only group IV rats showed persistent proteinuria. No alterations in lipid metabolism were present in any of the groups. The most striking findings in the micropuncture studies were a significant increase of glomerular capillary pressure in group IV rats (63.15 +/- 1.34 mm Hg) as compared to controls (48.74 +/- 0.97 mm Hg) and to groups II and III (55.31 +/- 2.11 and 48.17 +/- 1.23 mm Hg, respectively), and a marked fall in Kf in groups III and IV. Only group IV showed significant histological alterations such as glomerular sclerosis, interstitial damage, and increased glomerular area. These results suggest that, in the presence of an underlying nephropathy, a greater fraction of systemic pressure is transmitted to the glomerular capillaries when systemic hypertension is present; the resulting elevation in glomerular pressure and proteinuria seems to be responsible for the progression to glomerular sclerosis.

Response of atrial natriuretic factor to acute extracellular fluid volume in patients with pheochromocytoma.

BACKGROUND: Patients with pheochromocytoma have been reported to show high plasmatic atrial natriuretic factor (ANF) levels. Its source may not be the atrium because blood volume, the most important physiological stimulus for ANF release, is usually reduced in these patients. METHODS: To evaluate ANF secretion functional integrity, we studied three patients with pheochromocytoma before and after surgical removal of the tumor. Extracellular fluid (ECF) volume, plasmatic ANF levels, and plasmatic renin activity (PRA) were measured. ANF was measured before and after an acute saline load of 1.5L in 90 min. RESULTS: Before surgery, ECF volume was normal or reduced, and PRA was normal but decreased after the saline load. By contrast, ANF was elevated and did not change after the saline load. After surgery ANF decreased, ECF volume rose, and the saline load induced a significant increase of plasma ANF and reduction of PRA. ANF was present in significant amounts in tumoral tissue homogenates. CONCLUSIONS: These data suggest that the tumor was the source of ANF in these patients with pheochromocytoma because high levels of ANF, despite reduced or normal ECF volume, as well as unresponsiveness to acute saline infusion, were found before surgery with subsequent normalization after tumor removal.

[Role of prostaglandins in the antihypertensive effect of the converting enzyme inhibitor, enalapril]. / Papel de las prostaglandinas en el efecto antihipertensivo del inhibidor de la enzima convertidora, enalapril.

Angiotensin converting enzyme (ACE) generates angiotensin II and is also capable of degrading bradykinin into inactive peptides. It has been suggested that the effects of ACE inhibitors are partially mediated by increased prostaglandin synthesis induced by a simultaneous rise in bradykinin. Captopril increases PG excretion and indomethacin (INDO) attenuates its effects. Enalapril is a long acting ACE inhibitor, and its molecule does not have the sulphydryl group present in captopril. In order to evaluate the participations of PG in a the ENA effects of enalapril (ENA) on arterial pressure (AP), plasma renin activity (PRA), plasma aldosterone (ALDO) and renal hemodynamics (RH) in essential hypertension (EHT), we compared the effects of ENA alone and associated with INDO. Nine EHT patients received on different occasions: ENA 10 mg, INDO 25 mg and ENA-INDO. Arterial pressure, PGE2, ALDO, PRA, RH and plasma and urinary ENA as enalaprylate were measured after each treatment. Maximal ENA absorption occurred after 4 hours, however it was still detectable after 72 hr. ENA decreased AP after 6 hr in spite of unchanged PGE2 excretion; PRA did not change and ALDO decreased transiently. INDO delayed ENA absorption, slightly attenuated the fall in AP and suppressed PGE2 excretion when given with ENA. INDO alone suppressed PGE2 and did not alter AP. No significant changes occurred in RH with the treatments. Our results suggest that the antihypertensive effect of ENA is independent of PG, and that the slight attenuation induced by INDO may be attributed to a delay in intestinal absorption. In EHT patients under normovolemic conditions, renal function is not altered by ACE inhibition.

[Lipoprotein(a) and lipids in chronic renal insufficiency and kidney transplant]. / Lipoproteína(a) y lípidos en insuficiencia renal crónica y en trasplante renal.

OBJECTIVE: To establish the prevalence of lipid and lipoprotein (a) abnormalities in patients under hemodialysis or who underwent renal transplantation. METHODS: Forty dialyzed patients, 64 transplanted and a comparison group of 77 subjects of the general population paired by gender and age were studied. RESULTS: The most prevalent disorder in the hemodialysis was hypoalfalipoproteinemia followed by Lp(a) excess while the least common disorder was hypercholesterolemia. The transplanted patients had the lowest prevalence of Lp(a) excess and a higher proportion of hypercholesterolemia when compared to hemodialysis patients but similar to that of controls. CONCLUSION: Our results confirmed some previous findings observations of others but differed in that hypoalfalipoproteinemia and not hypertriglyceridemia was the predominant abnormality in the hemodialysis patients.

[Salt-dependent arterial hypertension]. / Hipertensión arterial dependiente de sal.

Almost 50% of essential hypertension is salt-sensitive, this characteristic increases and becomes more prevalent with age and is associated with a greater risk of cardiovascular a renal complications. The mechanism responsible for it has not been well established yet, although the participation of several vasoactive factors has been involved. Salt sensitivity implies an alteration in the relation between arterial pressure and sodium excretion or "pressure natriuresis", which is shifted to the right, that is, a higher blood pressure is required to maintain normal sodium excretion. Experimental studies suggest that this alteration is mediated by an increase in the resistance of preglomerular vessels due to hypertrophy of the vascular wall, decreased glomerular permeability, and enhanced tubular sodium reabsorption, as well as tubulointerstitial alterations that result in local release of vasoactive factors, cytokines, and growth factors, which, in turn, enhance glomerular hemodynamic alterations and impair sodium excretion.

[The regulatory mechanisms of glomerular filtration: the tubuloglomerular feedback system, physiological aspects and their participation in the physiopathology of kidney diseases]. / Mecanismos de regulación de la filtración glomerular: sistema retroalimentario tubuloglomerular, aspectos fisiológicos y su participación en la fisiopatología de enfermedades renales.

The tubuloglomerular feedback system (TGF), the main component of the autoregulation mechanism, maintains constant glomerular blood flow and filtration rate. The system is based in the morpho-functional association among the macula densa, the afferent and efferent arterioles, the glomerulus and the extraglomerular mesangial cells. The macula densa cells sense the changes in solute concentrations and osmolarity in the tubular fluid and send vasoconstrictor or vasodilatory signals to the arterioles that modify blood flow and glomerular filtration rate. However, the mechanism by which the macula densa sends signals to the arterioles remains unknown. A chemical mediator such as prostaglandins or adenosine has been postulated. Our studies discarded the participation of prostaglandins as mediators. Further studies from our group with adenosine analogs indicate that this nucleotide participates in the activation of the TGF responses, and suggest alternate activation pathways not previously described. To evaluate the role of TGF feedback in the glomerular hemodynamic changes associated with progression of renal damage, we studied TGF responses in rats with Goldblatt hypertension and partial ablation of the contralateral kidney. Our results suggest that the sensitivity of the system is decreased. This alteration may contribute to glomerular hypertension and progression to renal damage.

[Insulin resistance and hypertension]. / Resistencia a insulina e hipertensión.

It was recently suggested that insulin resistance present in diabetes and obesity may contribute to hypertension that frequently associates with both conditions. It has been proposed that the resulting hyperinsulinemia may induce hypertension through four possible mechanisms: Its trophic effect on vascular smooth muscle cells, increasing cytosolic calcium, increasing tubular sodium reabsorption or by stimulating adrenergic activity. Other studies however, did not confirm the ability of insulin to elevate blood pressure suggesting that the association between hypertension and hyperinsulinemia may no be a cause effect relationship, instead both phenomena may be secondary to the same cause. It has been suggested that adrenergic hyperactivity, changes in cellular ionic flux and alterations in microcirculation can induce both hypertension and insulin resistance.

Effect of captopril and hydrochlorothiazide on glomerular haemodynamics and histological damage in Goldblatt hypertension with partial renal ablation.

Increased glomerular capillary pressure (GCP) mediates glomerular damage in hypertension. The efficacy of captopril, an angiotensin converting enzyme (ACE) inhibitor, and captopril-hydrochlorothiazide (captopril-TZ) in lowering GCP and preventing glomerular damage was evaluated in rats with two-kidney, one clip (2K, 1C) Goldblatt hypertension and partial ablation of the unclipped kidney. Thirty days after surgery nine rats received captopril, 11 received captopril-TZ and eight served as untreated control rats. Sixty days later systemic hypertension was associated with increased GCP and severe structural damage in the unclipped kidney of C rats. Captopril lowered arterial pressure (AP), and prevented the rise in GCP and structural lesion. Captopril-TZ decreased AP and GCP to a greater extent, but did not reduce structural damage further. Captopril lowered GCP, preventing structural damage; greater reduction of GCP with captopril-TZ did not provide further protection.